LINC00662 promotes hepatocellular carcinoma progression via altering genomic methylation profiles
- 20 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (7), 2191-2205
- https://doi.org/10.1038/s41418-020-0494-3
Abstract
The identification of viability-associated long noncoding RNAs (lncRNAs) is a means of uncovering therapeutic approaches for hepatocellular carcinoma (HCC). In addition, aberrant genome-wide hypomethylation has been implicated in HCC initiation and progression. However, the relationship between lncRNA dysregulation and genome-wide hypomethylation in hepatocarcinogenesis has not been fully elucidated. A novel lncRNA named LINC00662 was previously demonstrated to play a role in gastrointestinal cancer. In this study, we demonstrated that this lncRNA was correlated with survival and exhibited oncogenic properties, both in vitro and in vivo. Moreover, we determined that LINC00662 could lead to genome-wide hypomethylation and alter the genomic methylation profile by synchronously reducing the S-adenosylmethionine (SAM) level and enhancing the S-adenosylhomocysteine (SAH) level. Mechanistically, LINC00662 was determined to regulate the key enzymes influencing SAM and SAH levels, namely, methionine adenosyltransferase 1A (MAT1A) and S-adenosylhomocysteine hydrolase (AHCY), by RNA–RNA and RNA–protein interactions. In addition, we demonstrated that some SAM-dependent HCC-promoting genes could be regulated by LINC00662 by altering the methylation status of their promoters via the LINC00662-coupled axes of MAT1A/SAM and AHCY/SAH. Taken together, the results of this this study indicate that LINC00662 could be a potential biomarker for HCC therapy. More importantly, we proposed a new role of lncRNA in regulating genomic methylation to promote oncogene activation.Funding Information
- National Natural Science Foundation of China (81800522)
This publication has 57 references indexed in Scilit:
- Control of somatic tissue differentiation by the long non-coding RNA TINCRNature, 2012
- Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclassesGenes & Development, 2011
- CpG islands and the regulation of transcriptionGenes & Development, 2011
- Forced Expression of Methionine Adenosyltransferase 1A in Human Hepatoma Cells Suppresses in Vivo Tumorigenicity in MiceThe American Journal of Pathology, 2010
- S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat modelHepatology, 2009
- S-adenosylhomocysteine hydrolase downregulation contributes to tumorigenesisCarcinogenesis: Integrative Cancer Research, 2008
- DNA methylation landscapes: provocative insights from epigenomicsNature Reviews Genetics, 2008
- The H19 Non-Coding RNA Is Essential for Human Tumor GrowthPLOS ONE, 2007
- Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosisInternational Journal of Cancer, 2007
- Inhibition of human betaine–homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosineBiochemical Journal, 2006